ABSTRACT The perimenopausal period can last more than a decade and is attended by significant morbidity including irregular reproductive cycles, dysfunctional uterine bleeding, urogenital changes, impaired fertility, declining bone mass, vasomotor symptoms, and psychological impairment. The first sign of ovarian aging is a rise in circulating FSH concentrations. We have identified that young women have high levels of hypo-glycosylated FSH21 while older women have high levels of fully-glycosylated FSH24. The biological activity of hypo- glycosylated FSH21 is much greater on the ovary where it binds efficiently to its receptor and stimulates estrogen production and follicle development. In contrast, the fully-glycosylated FSH24 has lesser effects at the level of the ovary, but has stimulatory effect on bone remodeling cells that promote osteoporosis. Thus, the changes in FSH glycosylation associated with aging and their actions in both traditional (ovarian granulosa cells) and non- traditional FSH target tissues (bone) requires immediate attention. The central hypothesis for this project is that in the face of a senescing ovary, the additional switch of hypo- to fully-glycosylated FSH further compromises reproductive potential and at the same time may hasten bone loss. The proposed Specific Aims will identify how and why the age dependent differences in FSH glycosylation alter the function of ovarian follicles and bone, a nontraditional FSH target. We will identify the specific intracellular signals that distinguish the action of hypo- glycosylated hFSH21 from the age-related fully-glycosylated FSH24 isoform. Mechanistic studies will demonstrate how these signals contribute to enhanced or reduced bioactivity in the ovary and bone. This project is innovative because it studies for the first time the impact of naturally occurring FSH glycoforms on the function of aging ovaries and on osteoclast formation in a nontraditional FSH target, bone. We are in an exclusive position to establish the mechanism of action of these novel FSH glycoforms using in vivo and in vitro models and multiple FSH target tissues. The impact of this work is that once we identify the unique biologic activities and functions of FSH glycoforms, we can then use this knowledge to develop strategies to maintain ovarian function and limit bone turnover. We have an outstanding team working in an outstanding environment, and have the tools necessary to complete this exciting and important project. Understanding how the age-dependent change in FSH glycoforms directs activities in multiple target tissue (ovary and bone) offers a unique opportunity to develop novel approaches to improve fertility and reduce age associated morbidity. This proposal has translational relevance that could be important for enhanced success for assisted reproductive technologies and the health of pre- and post-menopausal women.